Alternative Antigen Receptor (TCR) Signaling in T Cells Derived from ZAP-70-deficient Patients Expressing High Levels of Syk

Noraz, Nelly; Schwarz, Klaus; Steinberg, Marcos; Dardalhon, Valérie; Rebouissou, Cosette; Hipskind, Robert A.; Friedrich, Wilhelm; Yssel, Hans; Bacon, Kevin B.; Taylor, Naomi

doi:10.1074/jbc.m908568199

Cited by 60 publications

(69 citation statements)

References 41 publications

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“…However, despite increased Syk expression, the patient's cultured CD4 ϩ T cells were unresponsive to TCR-mediated stimuli. Although not identical, similar findings were reported recently in cultured T cells from two siblings homozygous for the mutation A507V, which abolishes both ZAP-70 expression and function (27). Despite increased Syk expression and rescue of SLP-76/ LAT/PLC␥1 phosphorylation and [Ca 2ϩ ] i mobilization after long term culture, induction of downstream signaling events, including Ras/MAPK activation and CD3-mediated IL-2 production, remained markedly defective in TCL from those patients (27).…”

Section: Survival Of the Patient's T Cells In The Circulation Is Not supporting

confidence: 62%

“…However, under normal circumstances, Syk appears to play a role for the most part in early ␣␤ T cell differentiation, whereas ZAP-70 function is critical for positive and negative selection in the thymus and T cell activation in the periphery. Our results differ from a recent observation that a subset of cultured primary T cells from SCID patients with a ZAP-70 null mutation are capable of proximal TCR signaling as a result of markedly increased Syk levels (27). We suggest that, despite increased Syk expression in a subset of our patient's TCL, the catalytically inactive ZAP-70 mutant is able to compete favorably for immunoreceptor tyrosine-based activation motif binding, thus inhibiting Syk phosphorylation of downstream effectors critical to activation of the calcium and Ras/MAPK pathways.…”

Section: Role Of Syk In Cd4 ϩ Thymocyte Selection In Human Zap-70 Defcontrasting

confidence: 56%

“…With the exception of one child who lacked ZAP-70 mRNA by Northern blot in whom the underlying mutation is not known (19) and another child with temperature-sensitive P80Q and M572L mutations (28), ZAP-70-deficient patients have inherited mutations within a small region of the ZAP-70 kinase domain that significantly affect both protein stability and catalytic activity. These included a 13-bp deletion resulting in a frame-shift after residue 503 and premature termination at amino acid 538 (16), two amino acid conversions, S518R (17) and A507V (27), and a splicing error that inserts LEQ into the protein after residue 541 (17,18).…”

Section: Novel Human Zap-70 Mutationmentioning

confidence: 99%

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Distinct T Cell Developmental Consequences in Humans and Mice Expressing Identical Mutations in the DLAARN Motif of ZAP-70

Elder

Skoda-Smith

Kadlecek

et al. 2001

The Journal of Immunology

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The protein tyrosine kinase, ZAP-70, is pivotally involved in transduction of Ag-binding signals from the TCR required for T cell activation and development. Defects in ZAP-70 result in SCID in humans and mice. We describe an infant with SCID due to a novel ZAP-70 mutation, comparable with that which arose spontaneously in an inbred mouse colony. The patient inherited a homozygous missense mutation within the highly conserved DLAARN motif in the ZAP-70 kinase domain. Although the mutation only modestly affected protein stability, catalytic function was absent. Despite identical changes in the amino acid sequence of ZAP-70, the peripheral T cell phenotypes of our patient and affected mice are distinct. ZAP-70 deficiency in this patient, as in other humans, is characterized by abundant nonfunctional CD4+ T cells and absent CD8+ T cells. In contrast, ZAP-70-deficient mice lack both major T cell subsets. Although levels of the ZAP-70-related protein tyrosine kinase, Syk, may be sufficiently increased in human thymocytes to rescue CD4 development, survival of ZAP-70-deficient T cells in the periphery does not appear to be dependent on persistent up-regulation of Syk expression.

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Section: Survival Of the Patient's T Cells In The Circulation Is Not supporting

confidence: 62%

Section: Role Of Syk In Cd4 ϩ Thymocyte Selection In Human Zap-70 Defcontrasting

confidence: 56%

Section: Novel Human Zap-70 Mutationmentioning

confidence: 99%

See 1 more Smart Citation

Distinct T Cell Developmental Consequences in Humans and Mice Expressing Identical Mutations in the DLAARN Motif of ZAP-70

Elder

Skoda-Smith

Kadlecek

et al. 2001

The Journal of Immunology

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“…ZAP-70-deficient patients express and signal via Syk. Syk high / ZAP-70 Ϫ T-cells show decreased Erk, JNK, and MAPK activity, suggesting a distinct signaling (17). T E cells in SLE patients show up-regulation of FcR␥-Syk signaling (18).…”

Section: Ics In Cd4mentioning

confidence: 99%

“…We also examined IFN-␥ production in P116 cells, a ZAP-70 mutant of Jurkat cells that can only signal via Syk (17 ϩ T-cells also showed pSyk (Fig. 8A).…”

Section: Icsϩc5b-9 Co-signal Triggers Expression Of Genes Associated mentioning

confidence: 99%

FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

Chauhan

Moore

et al. 2016

Journal of Biological Chemistry

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Zap70 inhibits Syk‐mediated osteoclast function

Zou

Croke

Fukunaga

et al. 2013

J of Cellular Biochemistry

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The αvβ3 integrin stimulates the resorptive capacity of the differentiated osteoclast (OC) by organizing its cytoskeleton via the tyrosine kinase, Syk. Thus, Syk-deficient OCs fail to spread or form actin rings, in vitro and in vivo. The Syk family of tyrosine kinases consists of Syk itself and Zap70 which are expressed by different cell types. Because of their structural similarity, and its compensatory properties in other cells, we asked if Zap70 can substitute for absence of Syk in OCs. While expression of Syk, as expected, normalizes the cytoskeletal abnormalities of Syk-/- OCs, Zap70 fails do so. In keeping with this observation, Syk, but not Zap70, rescues αvβ3 integrin-induced SLP76 phosphorylation in Syk-/- OCs. Furthermore the kinase sequence of Syk partially rescues the Syk-/- phenotype but full normalization also requires its SH2 domains. Surprisingly, expression of Zap70 inhibits WT OC spreading, actin ring formation and bone resorptive activity, but not differentiation. In keeping with arrested cytoskeletal organization, Zap70 blocks integrin-activated endogenous Syk and Vav3, SLP76 phosphorylation. Such inhibition requires Zap70 kinase activity, as it is abolished by mutation of the Zap70 kinase domain. Thus, while the kinase domain of Syk is uniquely required for OC function, that of Zap70 inhibits it.

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Alternative Antigen Receptor (TCR) Signaling in T Cells Derived from ZAP-70-deficient Patients Expressing High Levels of Syk

Cited by 60 publications

References 41 publications

Distinct T Cell Developmental Consequences in Humans and Mice Expressing Identical Mutations in the DLAARN Motif of ZAP-70

Distinct T Cell Developmental Consequences in Humans and Mice Expressing Identical Mutations in the DLAARN Motif of ZAP-70

FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

Zap70 inhibits Syk‐mediated osteoclast function

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